The Euro-Balance Trial: the effect of a new biocompatible peritoneal dialysis fluid (balance) on the peritoneal membrane.

BACKGROUND: Although peritoneal dialysis (PD) is a widely accepted form of renal replacement therapy (RRT), concerns remain regarding the bioincompatible nature of standard PD fluid. In order to evaluate whether a newly formulated fluid of neutral pH, and containing low levels of glucose degradation products (GDP), resulted in improved in vivo biocompatibility, it was compared in a clinical study to a standard PD fluid. METHODS: In a multicenter, open, randomized, prospective study with a crossover design and parallel arms, a conventional, acidic, lactate-buffered fluid (SPDF) was compared with a pH neutral, lactate-buffered, low GDP fluid (balance). Overnight effluent was collected and assayed for cancer antigen 125 (CA125), hyaluronic acid (HA), procollagen peptide (PICP), vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha (TNFalpha). Serum samples were assayed for circulating advanced glycosylation end products (AGE), N(epsilon)-(carboxymethyl)lysine (CML), and imidazolone. Clinical end points were residual renal function (RRF), adequacy of dialysis, ultrafiltration, and peritoneal membrane function. Eighty-six patients were randomized to either group I starting with SPDF for 12 weeks (Phase I), then switching to "balance" for 12 weeks (Phase II), or group II, which was treated vice versa. Seventy-one patients completed the study with data suitable for entry into the per protocol analysis. Effluent and serum samples, together with peritoneal function tests and adequacy measurements, were undertaken at study centers on three occasions during the study: after the four-week run-in period, after Phase I, and again after Phase II. RESULTS: In patients treated with balance there were significantly higher effluent levels of CA125 and PICP in both arms of the study. Conversely, levels of HA were lower in patients exposed to balance, while there was no change in the levels of either VEGF or TNFalpha. Serum CML and imidazolone levels fell significantly in balance-treated patients. Renal urea and creatinine clearances were higher in both treatment arms after patients were exposed to balance. Urine volume was higher in patients exposed to balance. In contrast, peritoneal ultrafiltration was higher in patients on SPDF. When anuric patients were analyzed as a subgroup, there was no significant difference in peritoneal transport characteristics or in ultrafiltration on either fluid. There were no changes in peritonitis incidence on either solution. CONCLUSION: This study indicates that the use of balance, a neutral pH, low GDP fluid, is accompanied by a significant improvement in effluent markers of peritoneal membrane integrity and significantly decreased circulating AGE levels. Clinical parameters suggest an improvement in residual renal function on balance, with an accompanying decrease in peritoneal ultrafiltration. It would appear that balance solution results in an improvement in local peritoneal homeostasis, as well as having a positive impact on systemic parameters, including circulating AGE and residual renal function.

Continuous dialysis with bicarbonate/lactate-buffered peritoneal dialysis fluids results in a long-term improvement in ex vivo peritoneal macrophage function.

To circumvent the potentially negative consequences of long-term exposure to unphysiologic acidic lactate-buffered peritoneal dialysis fluids (PDF), neutral pH solutions buffered with bicarbonate/lactate have recently been introduced in phase 2 and 3 clinical trials. This study examines the longitudinal changes in peritoneal macrophage (PMØ) function in patients dialyzed continuously with either lactate (LPD; 40 mM lactate, pH 5.2)-buffered or bicarbonate/lactate (TBL; 25 mM/15 mM bicarbonate/lactate, pH 7.3)-buffered PDF. Before the study, during the run in period of a phase 3 clinical trial, all patients had been taking LPD for at least the previous 18 wk. At the beginning of the study (day 0), both constitutive and serum-treated zymosan (STZ) stimulated tumor necrosis factor alpha (TNF-alpha) synthesis were assessed in PMØ isolated from 12-h dwell effluent (with 1.36% glucose) in all patients. The patients were subsequently randomized to either continuous TBL or LPD therapy and PMØ function was assessed after further 3- and 6-mo periods in all patients. At all time points measured STZ induced a dose-dependent increase in PMØ TNF-alpha secretion (P = 0.043 versus control for doses greater than 100 microg/ml). In patients continuously dialyzed with LPD, constitutive PMØ TNF-alpha synthesis levels (mean +/- SEM, pg/10(6) PMØ per18 h, n = 5 patients) were 154 +/- 65, 261 +/- 60, and 101 +/- 99 at 0, 3, and 6 mo, respectively. Stimulated STZ (1000 microg/ml) levels were 1340 +/- 519, 1046 +/- 586, and 758 +/- 250 at 0, 3, and 6 mo, respectively. In patients dialyzed with TBL, constitutive PMØ TNF-alpha synthesis levels (pg/10(6) PMØ per 18 h, n = 5 patients) were 300 +/- 136, 106 +/- 35, and 213 +/- 62 at 0, 3, and 6 mo, respectively. Stimulated STZ (1000 microg/ml) levels were 1969 +/- 751, 1541 +/- 330, and 2670 +/- 671 at 0, 3, and 6 mo, respectively. At 6 mo, STZ-stimulated PMØ TNF-alpha synthesis was significantly higher in patients treated with TBL compared with those treated with LPD (P = 0.0035). These data suggest that in patients continuously dialyzed with a neutral pH solution, there is a long-term improvement in PMØ function compared with patients on conventional therapy. Better PMØ function suggests improved host defense status and may affect the peritoneum's susceptibility to infection and potentially reduce the negative consequences of repeated intraperitoneal inflammation on long-term membrane function.

Morphologic changes in the peritoneal membrane of patients with renal disease.

This study examined the morphologic features of the parietal peritoneal membranes of 130 patients undergoing peritoneal dialysis (PD) and compared them with the features of the peritoneal membranes of normal individuals, uremic predialysis patients, and patients undergoing hemodialysis. The median thickness of the submesothelial compact collagenous zone was 50 microm for normal subjects, 140 microm for uremic patients, 150 microm for patients undergoing hemodialysis, and 270 microm for patients undergoing PD (P < 0.001 for all versus normal subjects). Compact zone thickness increased significantly with the duration of PD therapy [0 to 24 mo, 180 microm (n = 58); 25 to 48 mo, 240 microm (n = 24); 49 to 72 mo, 300 microm (n = 13); 73 to 96 mo, 750 microm (n = 16); >97 mo, 700 microm (n = 19)]. Vascular changes included progressive subendothelial hyalinization, with luminal narrowing or obliteration. These changes were absent in samples from normal subjects but were present in 28% of samples from uremic patients and 56% of biopsies from patients undergoing PD. In the PD group, the prevalence of vasculopathy increased significantly with therapy duration (P = 0.0001). The density of blood vessels per unit length of peritoneum was significantly higher for patients with membrane failure and was correlated with the degree of fibrosis (P = 0.01). For the first time, a comprehensive cross-sectional analysis of the morphologic changes in the peritoneal membranes of patients undergoing PD is provided. The infrequency of fibrosis in the absence of vasculopathy suggests that vasculopathy may predispose patients to the development of fibrosis. This study provides a sufficiently large cohort of samples to allow structure-function relationships to be established, as well as providing a repository of tissue for further studies.